RLS is a common, potentially disabling condition that affects about 10% to 15% of the general population and yet is often unrecognized and misdiagnosed. It is mainly diagnosed clinically and only rarely requires polysomnography. The condition is usually primary and treatable. First, however, secondary causes should be sought, especially iron deficiency and peripheral neuropathy, because when the source is an accompanying factor or condition, the syndrome may be curable.
RLS is a life-long condition for which there is no cure. Symptoms may gradually worsen with age, and their most disabling feature is the sleep onset insomnia they cause, which can be severe. RLS is a sensori-motor (movement) disorder characterized by uncomfortable sensations in the legs, which are worse during periods of inactivity or rest or while sitting or lying down. There is often a positive family history of the disorder. Individuals affected with the disorder describe the sensations as pulling, drawing, crawling, wormy, boring, tingling, pins and needles, prickly, and sometimes painful sensations that are usually accompanied by an overwhelming urge to move the legs. Sudden muscle jerks may also occur. Movement provides temporary relief from the discomfort. In rare cases, the arms may also be affected. Symptoms may interfere with sleep onset (sleep onset insomnia). Research suggests that RLS is related to periodic limb movement disorder (PLMD), another more common motor disorder which causes interrupted sleep. The symptoms often exhibit circadian rhythmicity in their peak occurrence during awakening hours.
A variety of etiologies have been proposed for RLS including pregnancy, polyneuropathy, spinal stenosis, Parkinson's disease, peripheral microembolism, and drug withdrawal from sedatives and vasodilators. While many mechanisms have been proposed for RLS, inflammation in the central nervous system associated and impaired blood flow to spinal nerve roots seems to be a common theme. RLS might result from the accumulation of irritants in the legs that are removed by leg movements. Changes in nerve conduction tests have also been reported in patients with RLS, suggesting abnormalities in spinal cord function. It has also been reported to reflect an autosomal dominant expression in families.
RLS has occurred in patients with and without painful neuropathies, and with alcoholic neuropathy, a painless neuropathy. RLS is not uniformly improved with analgesic drugs, like opioids, anti-convulsants, and others. RLS is improved with drugs used for treatment of movement disorders and not thought to have any analgesic properties (pergolide).
RLS is an independent predictor of mortality in dialysis patients, affecting up to 30%. There is no data available on whether this disrupter of sleep contributes to excess mortality in obese, diabetic, older females group outside of dialysis patients with greatest prevalence of RLS.
Neuroinflammation, which can contribute to chronic pain, may explain some of the mechanisms suggested for RLS. Neuroinflammation involves activation of endothelial cells, microglia and astrocytes, with subsequent production of cytokines, chemokines and the expression of surface antigens that enhance the immune, inflammatory and excitotoxic cascades. Activated glial cells synthesize proinflammatory mediators that act through NMDA receptors to enhance pain. At the spinal cord level, glial activation leads to the release of cytokines, chemokines and adhesion molecules. Alterations in blood flow and glial function in the central nervous system has been identified in pre-clinical acute and chronic pain studies.
Ketamine, a noncompetive N-methyl-D-aspatate (NMDA) receptor antagonist, in clinical use for almost 35 years, but has only recently been used in pain treatment. Ketamine is metabolized by hepatic cytochrome P450 system. The primary metabolite of oral ketamine is norketamine, which though one-third to one-fifth as potent as ketamine, contributes significantly to analgesia. Ketamine interacts with NMDA and a variety of other receptors, which affect analgesia. Ketamine inhibits activation of the NMDA receptor by glutamate, an excitatory neurotransmitter in CNS. Ketamine also reduces the presynaptic release of glutamate and potentiates the effects of the inhibitory neurotransmitter, GABA.
Inflammatory mediators produced locally by compression of nerve roots can activate neutrophils that then adhere to blood vessels and impair blood flow. Ketamine suppresses neutrophil production of inflammatory mediators and improve blood flow. Ketamine reduces the migration of leukocytes through endothelial cells due to influence on adhesion molecule expression. Direct inhibition of proinflammatory cytokines in the human whole blood by ketamine may also account for its anti-inflammatory actions.
Treatment for RLS is symptomatic. Massage and application of cold compresses may provide temporary relief. The most effective drugs are dopaminergic agents, clonazepam, opioids, gabapentin and clonidine. Additional agents are available that may be beneficial as add-on or alternative therapy. Medications such as temazepam, levodopa/carbidopa, bromocriptine, pergolide mesylate, oxycodone, propoxyphene and codeine are effective in relieving the symptoms. None of the existing treatments have anti-inflammatory effects. However, many of these medications have side effects. Accordingly, a method for treating the symptoms associated with RLS is needed which does not pose an undue risk of the occurrence of side effects and uses a different mode of action.